TAKAO HENSCH: LINKING NEUROSCIENCE AND SOCIETY

by
Charlie Schmidt

February 23rd, 2007

Takao Hensch

Takao Hensch thinks of himself as a bridge-builder, and since his work spans continents, languages, and schools on the Harvard campus, it’s easy to see why. A neuroscientist and new MCB professor, Hensch comes to Harvard from the RIKEN Brain Science Institute in Japan. At the age of 40, he’s already at the top of his field—a pioneer who’s done much to explain how the developing brains of infants and children wire themselves in response to their environments; a phenomenon called plasticity. He’s also shown that “critical periods” in plasticity—meaning times when brain rewiring is particularly susceptible—can be manipulated with drugs. That finding has propelled basic research and raised provocative medical issues: among the drugs that act on critical periods are sedatives such as valium, a treatment for seizures and other conditions in patients including the very young.

Hensch’s fascination with the brain stems back to his youth. In a remarkable upbringing, he grew up speaking three languages: German with his German father, Japanese with his Japanese mother, and English at school. The family moved to New York from Japan when Hensch was just two. His father, an engineer, had been transferred there by his employer, IBM. In elementary school, as he watched his young peers struggle with French classes, Hensch realized he could learn new languages more easily, and switch effortlessly among those he already knew. Even at a young age, he thought that ability came from his early exposure to languages, and the way that environment might have influenced the development of his brain.

As a Harvard undergrad, Hensch began a scientific journey that proved him right. Fueled by a passion for neuroscience, he chose biology as a major and worked with J. Allan Hobson, a Professor of Psychiatry who studies dreaming and sleep. “At Harvard I started working my way up the neuraxis,” Hensch says with a chuckle. The neuraxis refers to an imaginary line running from the spinal cord to the forebrain. With Hobson, Hensch started at the bottom in the brain stem, which controls basic functions like sleep, breathing, and motor coordination.

A Global Education

To study the cerebellum, the part of the brain that integrates senses and motor output, Hensch moved back to Japan. Earlier, he had been introduced by the late Harvard Professor Sandy Palay to Dr. Masao Ito, a famous Japanese scientist who views the brain as a neuronal machine. “Ito led that perspective,” Hensch says. “He wanted to understand the links between molecular elements, circuits, and systems function. I was extremely taken with that approach.” Though a Dean at the University of Tokyo, Ito had a westernized view of education, Hensch says. Foreign students were welcome in his lab, where Hensch soaked up all the brain physiology he could squeeze into a Master’s degree that he completed in 1991.

In Japan, Hensch felt himself drawn closer to the question that sparked his career in the first place: How does the environment shape the developing brain? To approach an answer, he shifted his attention further up the neuraxis to the cortex, and he moved to Germany for a year’s Fulbright Fellowship at the Max Planck Institute. There, he studied with Professor Wolf Singer, a renowned neurophysiologist who used the “ocular dominance model” in cats to study plasticity. With that model scientists cover one eye of an animal, causing brain circuits of the open eye to strengthen, while those serving the closed eye shrink. Unbalancing the intensity of environmental stimuli—for instance, by blocking visual input through one eye—thus weakens connections. Scientists had long assumed a reduced transmission of electrical messages, called long-term synaptic depression, or LTD, plays a key role. “It remains dogmatic to the field that something like LTD is bound to happen when connections get weak or are lost,” Hensch explains.

Neuronal circuits in the brain are shaped by experience
during critical periods in early life. A specific inhibitory
connection may trigger the onset of plasticity in the
visual cortex (large basket cell PV+).

While pursuing a PhD in California at UCSF, with Michael Stryker, Hensch tried to link weakened eye connections in the ocular dominance model to LTD. But those studies produced inconclusive results; LTD didn’t reveal the smoking gun he was hoping for. Out of frustration, he turned to an entirely different set of circuits: namely, those made up of inhibitory cells that block the activity of neurons, including—Hensch suspected—those involved in the plasticity. Inhibitory circuits work by releasing a chemical called GABA that binds to and then reduces the activity of target neurons. GABA, in turn, is synthesized by two sets of gene products: one called GAD67, which produces most of the body’s GABA stores, and another called GAD65, which provides a backup supply of the messenger. GAD67 is clearly necessary for life; mice that lack the gene die, Hensch says. But what about GAD65? What would be the effect on plasticity if this source was disabled?

A Clue Emerges

As he considered that question, good fortune reared its head: a different UCSF lab had just bred a GAD65 knockout mouse for diabetes research. The mouse didn’t produce striking results for diabetes studies, but for Hensch, the creature turned out to be very useful indeed. Closing one eye in the transgenic strain had no effect on brain wiring, showing that small reductions in GABA from disabling GAD65 could prevent plasticity from occurring.

About this time, a compelling offer came from Japan: Ito was launching the RIKEN Brain Science Institute and wanted Hensch to join him in Tokyo. It was 1996; Hensch was finishing his PhD. Would he come? After some deliberation, Hensch answered yes. “The best decision I could have ever made,” he says.

At RIKEN, Hensch confirmed GABA’s role in plasticity. By administering the sedative benzodiazepine, he could increase target neuron sensitivity to GABA, and mimic the effect of reactivating GAD65 in the knockout strain. As anticipated, benzodiazepines restored plasticity and produced the research model that Hensch still uses today.

Working with benzodiazepinesacross development, Hensch has since shown that critical periods can be activated with brief doses of valium, but only once in the animal’s life. What’s more, he’s shown that critical periods have a defined duration—those triggered prematurely with benzodiazepine also end prematurely. And by leveraging advances in molecular biology—particularly transgenic neurons that lack benzodiazepine sensitivity, or that fluoresce in the brains of living animals—he’s been able to identify which target cells likely need to be functional for plasticity to occur.

Implications for Society

Hensch now worries that by giving infants sedatives, doctors might inadvertently trigger critical periods too soon. He doesn’t yet know what the possible consequences could be. But from MCB and Children’s Hospital, he has excellent resources to study those questions and others raised by developmental disorders caused by critical periods gone awry, as perhaps in autism or schizophrenia.

Meanwhile, Hensch has begun to home in on plasticity relating to other sensory stimuli, including auditory systems that he studies in birds. “I’m dying to know how generalizable all this is,” Hensch says. “We have clear examples of critical periods in humans. Newborn Japanese babies can distinguish “R” from “L” but since they’re not exposed to those sounds in their native tongue they lose that ability within six months and they rarely get it back. Adults can adopt adaptive strategies, but that’s not what kids do; they physically rewire their brains to match their environments.” Hensch’s work has begun to identify the proteolytic processes downstream of GABA underlying the structural consolidation of early life experience.

Looking forward, Hensch is strengthening links between Harvard and the RIKEN Institute by initiating exchange programs for students. He’s also begun to collaborate with Dr. Jack Shonkoff, a pediatrician and professor at the Harvard School of Public Health. Shonkoff will direct a new Center on the Developing Child at Harvard, which unites issues in developmental neurology, education, ethics and other related fields.

“These are the kinds of opportunities I look for in a place like Harvard,” Hensch says. “Here, we’re able to move translationally from the nuts and bolts of neuroscience to their implications, which we can explore and discuss in a proactive way.”